This project assesses the efficacy and safety of new pharmacologic and biologic treatments for drug dependence using experimental paradigms in a controlled, residential environment. Some animal and open-label human studies suggest that the anti-convulsant carbamazepine may reduce cocaine craving and use, possibly by blocking the development of cocaine-induced kindling. However, a recently completed double-blind study did not support the efficacy of carbamazepine in the treatment of cocaine dependence. In humans, very low calorie diets producing ketonemia are associated with the absence of hunger, but it is not known whether this subjective effect also applies to drugs of abuse. In animals, balanced low calorie diets not producing ketonemia increase drug self-administration. A second component of this project is evaluating which of these dietary effects operates in human drug abusers, using nicotine (cigarette smoking) as the target drug. Preliminary results indicate that a balanced low calorie diet increases cigarette smoking, while a low calorie ketogenic diet does not alter smoking. These findings have clinical implications, especially since some drugs of abuse themselves suppress appetite and thus may produce calorie deprivation. The primary enzyme metabolizing cocaine in humans is butyrylcholinesterase. In theory, alterations in enzyme activity might alter brain levels of cocaine and its metabolites and thus alter cocaine's effects, with possible therapeutic benefits. In a collaborative study with the Preclinical Pharmacology Laboratory and the National Institute on Aging, compounds which alter butyrylcholinesterase activity are given to monkeys to determine whether they alter the acute effects of cocaine.